An expansive human regulatory lexicon encoded in transcription factor footprints

Shane Neph, Jeff Vierstra, Andrew B. Stergachis, Alex P. Reynolds, Eric Haugen, Benjamin Vernot, Robert E. Thurman, Sam John, Richard Sandstrom, Audra K. Johnson, Matthew T. Maurano, Richard Humbert, Eric Rynes, Hao Wang, Shinny Vong, Kristen Lee, Daniel Bates, Morgan Diegel, Vaughn Roach, Douglas Dunn, Jun Neri, Anthony Schafer, R. Scott Hansen, Tanya Kutyavin, Erika Giste, Molly Weaver, Theresa Canfield, Peter Sabo, Miaohua Zhang, Gayathri Balasundaram, Rachel Byron, Michael J. MacCoss, Joshua M. Akey, M. A. Bender, Mark Groudine, Rajinder Kaul and John A. Stamatoyannopoulos ()
Additional contact information
Shane Neph: University of Washington
Jeff Vierstra: University of Washington
Andrew B. Stergachis: University of Washington
Alex P. Reynolds: University of Washington
Eric Haugen: University of Washington
Benjamin Vernot: University of Washington
Robert E. Thurman: University of Washington
Sam John: University of Washington
Richard Sandstrom: University of Washington
Audra K. Johnson: University of Washington
Matthew T. Maurano: University of Washington
Richard Humbert: University of Washington
Eric Rynes: University of Washington
Hao Wang: University of Washington
Shinny Vong: University of Washington
Kristen Lee: University of Washington
Daniel Bates: University of Washington
Morgan Diegel: University of Washington
Vaughn Roach: University of Washington
Douglas Dunn: University of Washington
Jun Neri: University of Washington
Anthony Schafer: University of Washington
R. Scott Hansen: University of Washington
Tanya Kutyavin: University of Washington
Erika Giste: University of Washington
Molly Weaver: University of Washington
Theresa Canfield: University of Washington
Peter Sabo: University of Washington
Miaohua Zhang: Fred Hutchison Cancer Research Center
Gayathri Balasundaram: Fred Hutchison Cancer Research Center
Rachel Byron: Fred Hutchison Cancer Research Center
Michael J. MacCoss: University of Washington
Joshua M. Akey: University of Washington
M. A. Bender: Fred Hutchison Cancer Research Center
Mark Groudine: Fred Hutchison Cancer Research Center
Rajinder Kaul: University of Washington
John A. Stamatoyannopoulos: University of Washington

Nature, 2012, vol. 489, issue 7414, 83-90

Abstract: Abstract Regulatory factor binding to genomic DNA protects the underlying sequence from cleavage by DNase I, leaving nucleotide-resolution footprints. Using genomic DNase I footprinting across 41 diverse cell and tissue types, we detected 45 million transcription factor occupancy events within regulatory regions, representing differential binding to 8.4 million distinct short sequence elements. Here we show that this small genomic sequence compartment, roughly twice the size of the exome, encodes an expansive repertoire of conserved recognition sequences for DNA-binding proteins that nearly doubles the size of the human cis–regulatory lexicon. We find that genetic variants affecting allelic chromatin states are concentrated in footprints, and that these elements are preferentially sheltered from DNA methylation. High-resolution DNase I cleavage patterns mirror nucleotide-level evolutionary conservation and track the crystallographic topography of protein–DNA interfaces, indicating that transcription factor structure has been evolutionarily imprinted on the human genome sequence. We identify a stereotyped 50-base-pair footprint that precisely defines the site of transcript origination within thousands of human promoters. Finally, we describe a large collection of novel regulatory factor recognition motifs that are highly conserved in both sequence and function, and exhibit cell-selective occupancy patterns that closely parallel major regulators of development, differentiation and pluripotency.

Date: 2012
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DOI: 10.1038/nature11212

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